Tips from Other Journals
Treating Repetitive Seizures with Rectal Diazepam
Although rectal diazepam has been used on an outpatient basis in Europe for the treatment of severe, repetitive seizures for more than 20 years, such a formulation has only recently been labeled by the U.S. Food and Drug Administration for this purpose. Diazepam rectal gel is indicated for use in intermittent epilepsy to control bouts of increased seizure activity. Doses of diazepam rectal gel are individually packaged in pre-measured applicators for rectal insertion, ideal for use by caregivers in institutions or home settings. Cereghino and colleagues performed a multi-center, randomized, parallel, double-blind study to determine the safety and efficacy of the diazepam rectal formulation in patients with acute repetitive seizures.
In this study, caregivers were shown how to administer and monitor the medication by use of a video and illustrated written materials. Caregivers received close support and follow-up and had access to medical advice at all times. Response to the medication was measured by time until next seizure and seizure count, and through a global assessment completed by the caregivers and study investigators.
For study purposes, the epileptic seizure type included primary-generalized, complex-partial and simple-partial seizures with a motor component. These seizure types are believed to be the ones recognized more accurately by caregivers. Acute repetitive seizures were distinct from unpredictable seizures or those provoked by a specific cause in that they had a predictable pattern such as an aura or prodrome that distinguished them from other seizures in type, frequency, severity or duration. Most of the 114 patients included in the study were taking other seizure medications as well.
Analysis of seizure count showed that the median number of seizures in patients receiving diazepam was zero, whereas patients receiving placebo had a median of two seizures. In the 12-hour observation period following the administration of diazepam, 55 percent of patients were seizure free compared with 34 percent of those given placebo. The overall assessment by caregivers was also significantly higher in the diazepam group. Although no statistically significant difference in adverse events was found, there was an increased rate of somnolence in the patients receiving diazepam. No episodes of respiratory depression or withdrawal from the study because of adverse events occurred.
The authors conclude that it is possible for well-informed caregivers to predict and prevent acute repetitive seizures at home. The convenience and ease of use of diazepam gel treatment offers families more flexibility and control and may prevent costly emergency room visits and hospital stays.
CLARISSA C. KRIPKE, M.D.
Cereghino JJ, et al. Treating repetitive seizures with a rectal diazepam formulation. A randomized study. Neurology November 1998;51:1274-82.
Use of Colchicine in Patients with Severe Constipation
Constipation is the most common gastrointestinal complaint in the United States. It affects persons of all ages but is particularly troublesome in those who are elderly or disabled. Studies have shown that more than 50 percent of patients in nursing homes receive at least one laxative daily. Disabled patients may be constipated for several reasons, including autonomic dysfunction, poor oral intake, physical inactivity or as a side effect of medications. Colchicine, a medication commonly used to treat gout, is known to enhance gastrointestinal motility by neurogenic stimulation. Frame and colleagues performed a double-blind, crossover study to determine if daily administration of colchicine could improve bowel motility and reduce the need for laxatives in patients with severe constipation.
The 12 patients enrolled in the study were physically and mentally disabled adults who resided in residential care facilities and required three or more laxatives on a regular basis for more than six months. These patients had no contraindications to colchicine (specifically no hepatic or renal dysfunction). In addition, they were medically stable and had no life-threatening medical problems during the previous six months.
The trial lasted 22 weeks and was divided into four phases. During the first four weeks, the patients' laxative regimens were optimized to limit the number of doses while achieving at least three bowel movements per week. During the next eight weeks, the patients were divided into two groups: one group received oral colchicine in a dosage of 0.6 mg three times daily (or twice daily if the patient weighed less than 45 kg [99 lb]) and the second group was given an identical placebo. Phase three of the trial consisted of a two-week washout period. During phase four, the dosing was reversed, with the first group receiving placebo and the second group receiving colchicine for eight weeks. All patients were monitored clinically and by laboratory studies for any evidence of colchicine toxicity. Additional laxatives could be used as needed so that all patients would have at least three bowel movements per week. Data on the number of different laxatives and their dosages, and the frequency of bowel movements were recorded.
Eleven patients completed the study. Eight of the 11 patients experienced an increase in the number of bowel movements per week while receiving colchicine (range: three to 18). Overall, patients receiving colchicine had an average of 4.3 more bowel movements during the treatment period, a clinically, but not statistically, significant number because of the small sample size. Seven of the eight patients who had an increased number of bowel movements also required fewer doses of rectal laxatives. The colchicine was well-tolerated, with no reported incidents of nausea, vomiting, diarrhea or abdominal discomfort. Blood and stool monitoring were all within normal limits except for an elevated creatine kinase level in one patient during phase 2.
The authors conclude that colchicine apears to be a safe and effective adjunctive therapy for the management of patients with severe, intractable constipation who are resistant to standard therapies such as oral laxatives. Larger, prospective studies are needed to fully assess the long-term safety of this drug in the management of severe constipation.
JEFFREY T. KIRCHNER, D.O.
Frame PS, et al. Use of colchicine to treat severe constipation in developmentally disabled patients. J Am Board Fam Pract September/October 1998;11:341-6.
Chronic Depression: The Use of Cognitive Behavior Therapy
Most patients diagnosed with major depressive disorders experience recurrent episodes, despite treatment with antidepressant drugs or psychotherapy. Cognitive behavioral therapy has also been shown to be of benefit and results in lower relapse rates than standard clinical management. Fava and colleagues compared the effectiveness of cognitive behavioral therapy with that of clinical management in patients with recurrent depression.
Adults with a diagnosis of major depression that was confirmed by a psychiatrist and a clinical psychologist were eligible for the study. To be included in the study, patients had to have a history of three or more episodes of depression, with the immediately preceding episode occurring within the last 2 1/2 years, at least 10 weeks of remission between episodes and a minimum global severity score of 7 for the current episode of depression. Exclusion criteria included a history of manic, hypomanic or cyclothymic episodes, a history of active drug or alcohol abuse, and any active medical illness. Patients also had to have shown a successful response to a tricyclic antidepressant or a selective serotonin reuptake inhibitor. Patients with ratings of "better" or "much better" on a global scale of improvement following drug therapy were included in the study.
Patients were randomized to one of two treatment groups: pharmacotherapy plus cognitive behavioral therapy or pharmacotherapy plus standard clinical management. Patients in both groups attended 10 sessions of 30 minutes each, conducted every other week for 20 weeks. During that time, the medication was tapered so that by the last two sessions, none of the patients was receiving medication. Patients were then assessed every three months for the next two years, during which time no new medications or psychotherapeutic interventions were prescribed. Relapse was defined as the occurrence of an episode of major depression as established by the Research Diagnostic Criteria for a selected group of functional disorders.
Groups were composed of 20 patients. Demographic information and clinical characteristics were similar between groups. Patients in the group receiving cognitive behavioral therapy demonstrated significant improvement in residual symptoms of depression compared with patients in the group receiving standard clinical management. During the two-year follow-up period, five (25 percent) patients in the group receiving cognitive behavioral therapy experienced a relapse of major depression compared with 16 (80 percent) in the group receiving standard clinical management.
The authors conclude that cognitive behavioral therapy following successful treatment with antidepressants is effective in preventing relapses in patients with chronic depression. This conclusion challenges the assumption that long-term, high-dose drug treatment is the only way to prevent relapse in patients with recurrent depression. The amelioration of residual symptoms after successful medical therapy, as was accomplished with cognitive behavioral therapy, may be a key component in preventing relapse in patients with chronic depression.
JEFFREY T. KIRCHNER, D.O.
Fava GA, et al. Prevention of recurrent depression with cognitive behavioral therapy. Arch Gen Psychiatry September 1998;55:816-20.
Presentation of Abuse-Related Injuries Among Women
Because domestic violence and assault on women often go undetected, clinicians are increasingly being called on to improve their recognition of abuse. Abuse-related injuries have been reported to occur most commonly on the central regions of the body, such as the head, neck or trunk, whereas unintentional injuries have been reported to commonly affect peripheral regions. Fanslow and associates conducted a retrospective study to determine whether women presenting to the emergency department after assault differed from those who presented with unintentional injuries.
The study was performed at the emergency departments of two hospitals in New Zealand. Each injury was classified as an assault, a suicide attempt or an unintentional injury. Identification of assault was based on the patient's self-report or on the staff's suspicion and subsequent documentation.
Of the 2,966 study participants who presented with an injury, 260 (8.8 percent) were identified as having sustained injuries as a result of assault, and 2,428 were identified as having unintentional injuries. The remaining 278 women (9.4 percent) presented after a suicide attempt and were excluded from analysis.
The relationship between the victim and the perpetrator was unspecified in 130 cases of assault (50 percent). In 82 of the remaining cases of assault (63 percent), the perpetrator was found to be the woman's partner or ex-partner. Women in the assault group tended to be younger (mean age: 30 years) than those in the unintentional injury group (mean age: 42 years). Women with injuries as a result of assault tended to present at night and on weekends, whereas those with unintentional injuries were more likely to present between 6 a.m. and 6 p.m. on any day of the week.
Women with injuries resulting from assault were 13 times more likely than those with unintentional injuries to have sustained injuries to the head. Women with assault-related injuries were three times more likely to present with contusions or ill-defined signs and symptoms, such as pain in the limb, as women with unintentional injuries. A higher proportion of the women in the assault group left the emergency department without receiving medical care (6.9 percent versus 2.1 percent).
The authors conclude that women seeking medical care after assault are younger, have different sites of injury and more frequently leave the medical facility before evaluation and treatment are completed. The predictive power of specific indicators, however, appears to be poor. Consequently, the authors urge health care professionals to screen for abuse in all women presenting to the emergency department.
In an editorial accompanying the article, Abbott supports the authors' observation that patterns of injury or trauma do not predict domestic violence with useful accuracy. Abbott urges clinicians to document an adequate history, but questions universal screening for domestic violence among all women presenting to the emergency department. Injured patients should certainly be asked what happened, and strategies should be developed to prevent future episodes.
RICHARD SADOVSKY, M.D.
Fanslow JL, et al. Indicators of assault-related injuries among women presenting to the emergency department. Ann Emerg Med September 1998;32:341-8, and Abbott J. Assault-related injury: what do we know, and what should we do about it? [Editorial]. Ann Emerg Med September 1998;32:363-6.
Antibiotics for Bacterial Exacerbations of Bronchitis
Approximately one in five adults has chronic bronchitis. Acute bacterial exacerbation of this pulmonary disease is a common cause of hospitalization. Clinical manifestations of acute disease include increased daily cough and increased sputum production and purulence. About 50 to 60 percent of exacerbations are believed to be bacterial in origin (most commonly related to Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae). However, many physicians advocate the use of empiric antibiotic therapy in all patients with acute exacerbations of chronic bronchitis because of the potential for significant morbidity. Chodosh and colleagues performed a double-blind study comparing ciprofloxacin and clarithromycin to determine clinical and bacteriologic efficacy and safety of the two therapies. They also sought to compare the length of the infection-free interval between one acute exacerbation of chronic bronchitis and the next exacerbation.
Patients enrolled in the study included adults at least 18 years of age who had a history of chronic bronchitis associated with chronic asthma, chronic obstructive pulmonary disease (COPD), or both, as defined by the American Thoracic Society. The patients had to present with an increase in dyspnea, sputum volume and purulence, and they had to have a documented fever (temperature higher than 38.0°C [100.4°F]), increased wheezing or increased cough compared with baseline. Bacterial infection was documented by the presence of 25 or more leukocytes per low-power field and the presence of a likely bacterial pathogen on Gram stain. Patients who were more severely ill, including those with an infiltrate present on chest radiograph, a history of immunodeficiency or a need for parenteral antibiotics were excluded from the study. Patients were randomized to receive two 250-mg tablets of either ciprofloxacin or clarithromycin, which were identical in appearance. The antibiotics were administered twice daily for 14 days. The use of expectorants and bronchodilators was permitted. The effectiveness of the antimicrobial agents was assessed by patient clinical response and laboratory measurements, with a physical examination at two, 12, 24 and 36 weeks post-treatment--or when a treatment failure or a new exacerbation ocurred.
A total of 376 patients were initially randomized into the study. Approximately one-third of the patients were smokers; otherwise no significant differences existed between the two groups. Two hundred and eleven patients completed the study (the efficacy-valid population); however, the other 162 patients were included in the intention-to-treat analysis arm of the study. In the efficacy-valid population, 90 percent of the ciprofloxacin patients and 82 percent of the clarithromycin patients had clinical resolution of symptoms by day 14. Throughout the 36-week follow-up period, 55 percent of the ciprofloxacin patients and 59 percent of the clarithromycin patients experienced a relapse or a new exacerbation. The median length of infection-free interval was 142 days in the ciprofloxacin group and 51 days in the clarithromycin group. Bacterial eradication at the end of therapy was 91 percent in the ciprofloxacin group but only 77 percent in the clarithromycin patients.
The authors conclude from this study that patients taking ciprofloxacin showed a longer infection-free interval than did those treated with clarithromycin. In addition, ciprofloxacin is more effective at producing bacterial eradication than clarithromycin and appears to be favored as first-line therapy for treatment of chronic bronchitis.
JEFFREY T. KIRCHNER, D.O.
Chodosh S, et al. Efficacy of oral ciprofloxacin vs. clarithromycin for treatment of acute bacterial exacerbations of chronic bronchitis. Clin Infect Dis October 1998; 27:730-8.
EDITOR'S NOTE: This study, although performed in a select group of high-risk patients, is consistent with a trend in the literature showing that the quinolones may be a good alternative as first-line treatment for acute lower respiratory infections. In the same issue of this journal, a second study shows similar results in the same subtype of patients treated with either ciprofloxacin or cefuroxime axetil, a second-generation cephalosporin. Also of note, several of the newer quinolone antibiotics have better efficacy against Streptococcus pneumoniae, compared with ciprofloxacin. These antibiotics also cover Chlamydia species and Mycoplasma species. The most recent guidelines from the Infectious Diseases Society of American list this class of drugs as a second-line choice for treating community-acquired pneumonia. The concern of many physicians remains the cost of these agents and their potential for promoting bacterial resistance.
J.T.K.
Types of Pituitary Tumors and Management Strategies
Pituitary tumors account for 10 percent of all intracranial tumors. Because these tumors are often curable, accurate diagnosis is important. Magnetic resonance imaging (MRI) with gadolinium enhancement has greatly improved pituitary visualization. The goals of treatment include normalization of pituitary secretion, alleviation of symptoms and signs, and shrinkage or elimination of large tumors that might compress vital structures. Shimon and Melmed review the management of pituitary tumors (see the accompanying table).
The authors used the MEDLINE database to search for relevant literature on pituitary tumors. Prolactinoma, the most common hormone-secreting pituitary tumor, accounts for approximately 60 percent of functioning tumors. These tumors are characterized by mildly elevated serum prolactin levels accompanied by amenorrhea, infertility and galactorrhea in women, and higher prolactin levels are accompanied by impotence, loss of libido or infertility in men. Initial medical therapy consists of a dopamine agonist (cabergoline or bromocriptine). Patients should be monitored by regular measurements of serum prolactin levels, pituitary MRI and visual field examinations. Discontinuation of therapy often results in recurrent hyperprolactinemia. Surgery is infrequently necessary for resistant tumors.
Management and Control of Hormone Hypersecretion in Pituitary Adenomas
Type of tumor
Primary approach*
Secondary approach*
Novel medical developments
Prolactin- secreting tumors Dopamine agonists: microadenomas, 80% to 90% response; macroadenomas, 60% to 75% response Surgery: microadenomas, 55% response; macroadenomas, 20% response Depot long-acting dopamine agonists; somatostatin receptor subtypeselective analogs Growth hormone secreting tumors Surgery: microadenomas, 70% response; macroadenomas, 50% response Somatostatin analogs, 60% response; dopamine agonists, 20% response; irradiation, 50% response (by 12 years) Long-acting somatostatins; somatostatin receptor subtype selective analogs; growth hormone receptor or GHRH antagonist ACTH-secreting tumors Surgery: microadenoma, 80% to 90% response; macroadenoma, 50% response Irradiation plus cortisol- decreasing drugs TSH-secreting tumors Surgery plus irradiation, 67% response Somatostatin analogs, 75% response Long-acting somatostatins Nonfunctioning tumors Surgery: improved vision, 70% response Irradiation Gonadotropin-releasing hormone antagonists
GHRH=growth hormonereleasing hormone; ACTH=adrenocorticotropin hormone; TSH=thyroid-stimulating hormone.
*--Response refers to normalization of hormone secretion or ablation of tumor mass.
Reprinted with permission from Shimon I, Melmed S. Management of pituitary tumors. Ann Intern Med September 15, 1998;129:472-83.
Growth hormonesecreting adenomas account for 20 percent of functional pituitary tumors. They are often macroadenomas and present with parasellar or suprasellar invasion. Because symptoms of acromegaly develop slowly, diagnosis may be delayed for seven to 10 years. Headaches, hypopituitarism and visual disturbances are common manifestations. Surgery is the preferred treatment for growth hormonesecreting adenomas. Somatostatin analogs such as octreotide, which suppress growth hormone secretion, may be used as adjuvant therapy or, in selected cases, as primary treatment. Combined treatment with octreotide and bromocriptine has an additive effect on suppression of growth hormone and insulin-like growth factor I. Bromocriptine has increased bioactivity when administered with octreotide. Sellar irradiation may be used in patients resistant to medical management, but it has a slow response rate (five to 10 years) and a high rate of late hypopituitarism.
Adrenocorticotropin-secreting tumors constitute 15 percent of functional pituitary adenomas. These tumors are usually treated surgically. Transsphenoidal adenomectomy has a cure rate of 80 to 90 percent for microadenomas, but the rate is up to only 50 percent for macroadenomas. Hypopituitarism with permanent hypocortisolism may occur following surgery. If surgery fails to control the condition, pituitary irradiation, possibly combined with medical treatment, can be used. Adjuvant drug therapies include the adrenolytic agent mitotane, ketaconazole, aminoglutethimide and metyrapone, which decrease cortisol levels without affecting adrenocorticotropin hormone levels. Mitotane therapy combined with irradiation is the preferred treatment if surgical treatment fails.
Adenomas secreting thyroid-stimulating hormone (TSH) are rare and result in secondary hyperthyroxinemia and goiter. Surgical excision or debulking is the treatment of choice. Antithyroid medications are not used because of the possibility of increased tumor growth and aggressiveness from the release of the thyrotroph cell from thyroid feedback inhibition. Treatment with a somatostatin analog, such as octreotide, can reduce TSH production when surgery and radiation therapy are not effective. Dopamine agonists are not effective in suppressing TSH secretion from these tumors.
Nonfunctioning pituitary adenomas (gonadotroph-cell adenomas) account for approximately one third of all pituitary tumors and are the most common macroadenomas. The presentation of these tumors is determined by local mass effects, including optic chiasm pressure, neurologic symptoms and deficient pituitary hormone secretion. Hypogonadism may be present. Transsphenoidal surgery is the only way to decrease tumor size and relieve mass effects. These tumors have shown poor response to drug treatment.
RICHARD SADOVSKY, M.D.
Shimon I, Melmed S. Management of pituitary tumors. Ann Intern Med September 15, 1998;129:472-83.
Oral vs. Transdermal HRT to Reduce Lipoprotein(a) Levels
Lipoprotein(a) [Lp(a)] contains structural elements similar to low-density lipoprotein (LDL) and plasminogen that may impart both atherosclerotic and thrombogenic activity. Epidemiologic investigations have reported that Lp(a) plasma levels are higher in postmenopausal women than in premenopausal women. Treatment of postmenopausal women with hormonal therapy has been shown to significantly lower Lp(a) levels, by up to 50 percent. Meschia and associates conducted a prospective randomized trial to compare the effects of oral and transdermal hormone replacement therapy on Lp(a) and other plasma lipid levels in healthy postmenopausal women.
A total of 120 postmenopausal women were randomized to one of two therapeutic regimens: 60 women received 17b-estradiol transdermal patches, in a dosage of 50 mg daily, plus medroxyprogesterone acetate (MPA), in a dosage of 10 mg daily for 12 days every three months; the other 60 women received oral conjugated equine estrogen in a dosage of 0.625 mg daily plus MPA, in a dosage of 10 mg daily for 12 days every three months. Forty-one women served as control subjects. Baseline clinical characteristics were similar in both groups.
The mean plasma Lp(a) level decreased significantly (22 percent) after three months in women receiving oral estrogen, but no further decrease was observed after six and 12 months of therapy. Women treated with transdermal estrogen also showed a significant decrease (12 percent) in Lp(a) levels after three months. No further reduction in Lp(a) levels was observed after six and 12 months of therapy. The Lp(a) levels in the control group remained unchanged during the study period.
Plasma concentrations of total cholesterol were decreased with both transdermal and oral estrogen after three months of treatment. No additional reduction was demonstrated at six and 12 months. The LDL-cholesterol levels were decreased significantly with both treatments after three months of therapy. Increases in high-density lipoprotein (HDL) cholesterol were seen throughout the study in the group receiving oral estrogen. However, HDL levels did not change during transdermal estradiol therapy.
Results of this study demonstrate that both oral and transdermal hormone replacement therapy reduces the serum concentration of Lp(a) in postmenopausal women. Oral conjugated estrogen decreased Lp(a) levels by 22 percent after three months of treatment, but no further reduction was seen during the following months, confirming that the lowering effect is achieved soon after initiation of therapy and that there is no additive effect over time. For this study, both estrogen regimens were combined with oral MDA, which, when administered at 10 mg daily for 12 days every three months, had negligible effects on the antiatherogenic effects of estrogen.
The authors conclude that both oral and transdermal hormonal therapy effectively lower Lp(a) in postmenopausal women. The findings suggest that the hepatic first-pass of estrogen does not influence to a greater extent the effect of hormone replacement therapy on Lp(a) plasma concentrations. Lengthening the treatment interval also does not appear to achieve better outcomes. The addition of a progestational agent was not associated with any negative or confusing effects on lipoprotein levels.
BARBARA APGAR, M.D., M.S.
Meschia M, et al. Effects of oral and transdermal hormone replacement therapy on lipoprotein(a) and lipids: a randomized controlled trial. Menopause Fall 1998;5:157-62.
Captopril or Atenolol for Hypertension in Diabetes?
Tight control of blood pressure in patients with type 2 diabetes mellitus (formerly known as non-insulindependent diabetes mellitus) significantly reduces both microvascular and macrovascular complications. When blood pressure is controlled, the risk of stroke is reduced by 44 percent, the risk of microvascular disease is reduced by 37 percent and the risk of any diabetes-related complication is reduced by 24 percent. Beta-blocking agents and angiotensin converting enzyme (ACE) inhibitors have potential advantages in hypertensive patients with diabetes. ACE inhibitors may have a protective effect on renal microvascular disease and reduce heart failure mortality. Beta blockers reduce cardiac mortality after myocardial infarction and are effective in treating heart failure. The UK Prospective Diabetes Study Group directly compared the efficacy of captopril and atenolol in reducing the incidence of clinical complications in hypertensive patients with type 2 diabetes.
Patients were recruited as part of a large multicenter study of diabetes treatments involving 20 centers in Britain. Of the hypertensive patients with type 2 diabetes allocated to "tight" control, 400 were allocated to captopril therapy and 358 to atenolol therapy. Captopril was started at a dosage of 25 mg twice daily, increasing to a dosage of 50 mg twice daily; the goal was to achieve a systolic blood pressure less than 150 mm Hg and a diastolic blood pressure less than 85 mm Hg. Atenolol was started at a dosage of 50 mg daily, increasing to 100 mg daily if necessary. If control was not achieved, other agents were added in sequence, beginning with furosemide, followed by slow-release nifedipine, methyldopa and prazosin. Patients were monitored for control of diabetes, hypertension and evidence of any of 21 clinical end points. The duration of follow-up was nine years.
The two groups of patients were similar in age, body mass index, clinical status, and severity of diabetes and hypertension. Patient compliance was similar in both groups during the first four years of the study, but significantly more patients discontinued using atenolol later in the study. Overall, 80 percent of those assigned to captopril and 74 percent of those assigned to atenolol received treatment during the entire follow-up period. Three or more agents were required to achieve control in 27 percent of the captopril patients and in 31 percent of the atenolol patients. The two groups of patients achieved similar reductions in blood pressure (the captopril group to 144/83 mm Hg and the atenolol group to 143/81 mm Hg); patients who were not assigned to "tight" control--and thus did not take captopril or atenolol--had a mean blood pressure of 154/87 mm Hg over the nine-year period. Patients allocated to atenolol gained slightly more weight and had slightly higher glycated hemoglobin concentrations during the first four years of the study.
The incidence of all deaths and deaths associated with diabetes was similar in both groups. In addition, no statistically significant differences were found in any of the clinical end points. In each of the major categories of macrovascular disease, atenolol showed slight advantages over captopril, but none that came close to statistical significance. After nine years of follow-up, 31 percent of patients in the captopril group and 37 percent of those assigned to atenolol showed deterioration in retinopathy. Clinical albuminuria developed in 5 percent of patients in the captopril group and in 9 percent of patients in the atenolol group. These measures of renal function as well as others showed no statistical differences between the two treatments.
The authors conclude that both agents effectively and safely lower blood pressure and reduce the risk of fatal and nonfatal microvascular and macrovascular complications in patients with diabetes. The specific renal protection of ACE inhibitors was not apparent in this study. The choice of agent should be made on an individual basis for hypertensive patients who have type 2 diabetes.
ANNE D. WALLING, M.D.
UK Prospective Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ September 12, 1998;317:713-20.
EDITOR'S NOTE: September issues of the two major British journals, BMJ and Lancet, contain several papers and commentary on type 2 diabetes. This condition is so prevalent in practice that there is a tendency to become complacent about its power to harm patients and to adopt a generally less aggressive attitude toward its management. The prevalence of type 2 diabetes is expected to increase and the total number of people affected worldwide is expected to rise from 110 million to over 200 million by the year 2010. These people will be at substantial risk for multiple conditions caused or exacerbated by diabetes. In particular, the 40 percent of patients who also become hypertensive before 45 years of age are at significant risk for vascular disease. Current reports validate the benefits of controlling blood glucose and blood pressure levels. Long-term studies showed reductions of over 40 percent in stroke and 30 percent in retinopathy, and reductions in multiple other end points, and in circumstances similar to most practice environments. This good news should re-energize efforts to manage patients with type 2 diabetes in everyday practice. The studies also indicate that we are on the threshold of a much more sophisticated approach to this common condition. Rather than taking a "one hypoglycemic agent fits all" approach, the next decade is likely to provide the information and medication necessary to tailor therapy to specific characteristics of each patient. Although we will be managing a greater number of patients with diabetes in the future, we can look forward to providing each with a regimen that offers real prospects of vigorous daily life and minimal risk of catastrophic complications.
A.D.W.
Folate and Colon Cancer: Data from the Nurses' Health Study
Folate is essential for the production of purines and pyrimidines, which are required for DNA synthesis. An inadequate supply of folate may lead to abnormalities in DNA synthesis or repair. Data from prospective studies of men suggest that an inadequate intake of folate may increase the risk of colon cancer. Giovannucci and associates examined the relationship between folate intake, both from supplements and from food, and the risk for colon cancer in women participating in the Nurses' Health Study.
The dietary cohort (88,756 women) in this longitudinal study was established in 1980 by eliciting information on a food-frequency questionnaire that included items on 61 foods and beverages, and the use of vitamin and mineral supplements. Similar but expanded questionnaires were obtained in 1984, 1986 and 1990. Participants also provided information on height and weight, physical activity, aspirin use, colonoscopic or sigmoidoscopic screening for colon cancer and parental history of colon cancer.
A total of 655 new cases of colorectal adenocarcinoma were confirmed in the cohort. Of these, 442 lesions were in the colon, 143 were in the rectum and 70 were at undetermined sites.
Analysis of the total, supplemental and dietary intake of folate in relation to the risk of colon cancer demonstrated that a higher (more than 400 mg per day) total intake of folate in 1980 was related to a lower risk for colon cancer in women as compared with the risk among women with an intake of 200 mg per day or less. When data were analyzed to determine the influence of other nutrients, including vitamins A, E, C and D, and calcium, none of these nutrients was significantly related to the risk of colon cancer. For folate obtained from food only, a nonsignificant inverse association was noted when long-term (15 years or more) supplement users were excluded. However, long-term multivitamin use was associated with a substantially lower risk of colon cancer across all levels of dietary folate.
According to the authors, the results indicate that the long-term use (for 15 years or more) of multivitamin supplements containing folic acid may decrease colon cancer risk by about 75 percent, consistent with the hypothesis that folate intake is the principal nutritional factor associated with risk reduction. The findings indicate that both dietary and supplemental intakes are beneficial. In view of the relationship between folic acid intake and prevention of neural tube defects, along with possible benefits in preventing cardiovascular disease, the observations from this study of folate intake and risk of colon cancer in women raise the question of whether a higher folate intake in the general population may be a worthwhile goal.
RICHARD SADOVSKY, M.D.
Giovannucci E, et al. Multivitamin use, folate, and colon cancer in women in the Nurses' Health Study. Ann Intern Med October 1, 1998:129;517-24.
Acute Sinusitis: Are Expensive Antibiotics More Efficacious?
Acute sinusitis is a common infection, usually attributed to Streptococcus pneumoniae, Haemophilus influenzae and, less often, Moraxella catarrhalis. As these organisms are generally susceptible to less expensive antibiotics such as amoxicillin and co-trimoxazole (trimethoprim plus sulfamethoxazole), de Ferranti and colleagues questioned the role of the more expensive broad-spectrum antibiotics and conducted a meta-analysis to compare the two types of antibiotics.
The authors searched Medline and other sources for randomized trials of treatment of acute sinusitis or acute exacerbations of chronic sinusitis that compared amoxicillin or a folate inhibitor with another antibiotic. The trials were examined for quality based on randomization, blinding, description of patient follow-up, clinical outcomes and use of decongestants. Of the 80 trials identified, only 27 met the study criteria. Six of these trials were placebo-controlled, 13 compared amoxicillin with other antibiotics and eight compared a folate inhibitor (e.g., co-trimoxazole or trimethoprim plus sulfametopyrazine) with other antibiotics. The trials involved 2,717 patients with a mean age of 25 to 44 years (in all but two trials). The trials differed in the use of decongestants, the diagnostic criteria for sinusitis and the definitions of outcomes.
In studies comparing any antibiotic with placebo, antibiotics reduced the number of treatment failures by almost one half, but symptoms resolved in 69 percent of patients treated with placebo. When amoxicillin was compared with other antibiotics, no significant differences were found in the rate of cure or failure. The authors calculate that treating 100 cases of acute sinusitis with amoxicillin instead of a more expensive antibiotic would lead to less than one additional treatment failure. Similar results were obtained with folate inhibitors, but the conclusions were limited by the relatively small number of cases studied. Because of the wide differences between the studies, no meaningful conclusions can be drawn concerning radiographic and bacteriologic evidence of cure. It was noted that approximately two thirds of cases of acute sinusitis improve spontaneously with no antibiotic therapy.
The authors conclude that traditional antibiotics, such as amoxicillin and folate inhibitors, have similar efficacy to newer medications and could decrease the development of antibiotic resistance in bacteria and reduce the costs of treating this common condition.
ANNE D. WALLING, M.D.
de Ferranti S, et al. Are amoxicillin and folate inhibitors as effective as other antibiotics for acute sinusitis? A meta-analysis. BMJ September 5, 1998;317:632-7.
Can Valaciclovir Suppress Recurrent Genital HSV?
Genital herpes simplex virus (HSV) infections continue to be a significant problem, particularly in sexually active young adults. After the initial episode of the infection, over 90 percent of patients have clinical recurrence of the infection. Suppressive therapy with acyclovir has been established as both safe and effective in managing recurrent episodes of HSV infection. The recommended dosage for acyclovir is 400 mg twice daily. Valaciclovir is a newer antiviral agent that, because of its greater bioavailability, may be effective in suppressive therapy using once-a-day dosages. Reitano and associates examined the efficacy and safety of various dosage schedules of valaciclovir compared with acyclovir and placebo in the treatment of recurrent genital herpes.
Men and women with a history of six or more genital HSV recurrences per year were enrolled in a multicentered, randomized, double-blind trial. To be included in the study, patients had to have documented genital HSV infection and a history of recurrent episodes. Those already taking suppressive therapy had to stop taking medication for three months before the study. The patients were divided into two groups, those with a history of fewer than 10 recurrent HSV episodes and those with 10 or more recurrences. The six treatment arms of the study included valaciclovir in dosages of 250 mg once daily, 500 mg once daily, 1 g once daily or 250 mg twice daily, acyclovir in a dosage of 400 mg twice daily, and placebo. Treatment lasted for one year. All patients were evaluated before the study and monthly during the study. The patient was evaluated within 24 hours of a recurrence. If a recurrence was documented, the patient was given episodic valaciclovir for five days. Patients kept diaries to record recurrences, use of concomitant medications and adverse side effects.
A total of 1,479 patients enrolled in the study; 1,050 patients completed the protocol. The demographics were similar in all the treatment groups. With regard to efficacy, all treatment groups were better than the placebo group. Patients who received valaciclovir and acyclovir twice daily showed no difference in the number of recurrences. In patients with a history of 10 or more recurrent episodes of genital herpes per year, the most effective dosage of valaciclovir was 1 g per day. In patients with less than 10 recurrent episodes annually, valaciclovir in a dosage of 500 mg once daily was as effective as a dosage of 1 g daily. The results of these regimens were similar to those of a regimen of acyclovir twice daily. The incidence of adverse outcomes in all of the regimens, including placebo, were similar. Most of the adverse effects were mild and well-tolerated; the most frequent side effects were headache, rhinitis, infection and flu-like syndrome.
The authors conclude that the study supports the use of valaciclovir as suppressive therapy for recurrent genital HSV infections. In patients with a history of less than 10 recurrent episodes per year, 500 mg of valaciclovir once daily is the appropriate starting dosage. In patients with more frequent recurrences, valaciclovir, in a dosage of 1 g daily or 250 mg twice daily, or acyclovir, in a dosage of 400 mg, would be the most effective therapy.
KARL MILLER, M.D.
Reitano M, et al. Valaciclovir for the suppression of recurrent genital herpes simplex virus infection: a large-scale dose rangefinding study. J Infect Dis September 1998; 178:603-10.
Sertraline Is Safe and Effective in Treating Panic Disorder
The treatment of panic disorder with tricyclic antidepressants, monoamine oxidase inhibitors and benzodiazepines has been proved to be effective. Each of these classes of medications has drawbacks, including side effects and, in the case of benzodiazepines, addiction potential. Selective serotonin reuptake inhibitors (SSRIs) have a pharmacologic and therapeutic profile that could offer an advantage over the other medications in treating panic disorder. Pohl and colleagues studied the efficacy and safety of sertraline, an SSRI, in the treatment of panic disorder.
The study was a double-blind, randomized, parallel-group design with a flexible dosage schedule comparing sertraline to placebo. Patients with an established diagnosis of panic disorder based on the Diagnostic and Statistical Manual of Mental Disorders, 3rd ed. (DSM III-R) guidelines were included in the study. Patients also had to have at least one unanticipated panic attack within four weeks of the start of the trial. After a two-week lead-in period with placebo, the patients were randomized to either the treatment or the placebo group. The treatment group began taking sertraline in a dosage of 25 mg per day for one week, then, with flexible titration, 50 to 200 mg per day. During and after the study period, patients were evaluated for symptoms, number of panic attacks and duration of anticipatory anxiety regarding the panic attack. Side effects were also monitored in both groups.
A total of 168 patients were enrolled in the study. There were no differences between the placebo and treatment groups with regard to baseline demographics, clinical characteristics or social functioning. In the sertraline treatment group, 9 percent of the patients stopped taking the medication because of side effects; only 1 percent stopped because of lack of efficacy. A significant number of patients in the treatment group experienced a decrease in the frequency of panic attacks, with 62 percent of the treated patients remaining free of any attacks at the end of the study period. The treatment group also had a decrease in the severity of symptoms during an attack and reported less anxiety before the attacks. The most common adverse events were gastrointestinal in nature (33 percent reported nausea, and 24 percent reported diarrhea). Dry mouth was reported by 19 percent of the patients; other adverse events included ejaculation failure (11 percent) and decreased libido (10 percent). The authors conclude that sertraline is a well-tolerated and highly effective treatment for panic disorders. Therapeutic responses occurred rapidly and without a notable risk of jitteriness with a 25-mg starting dosage. Sertraline appears to be most effective at a dosage of 50 to 200 mg.
KARL MILLER, M.D.
Pohl RB, et al. Sertraline in the treatment of panic disorder: a double-blind multicenter trial. Am J Psychiatry September 1998;155:1189-95.
Gestational Diabetes: Screening in Low-Risk Women?
The American Diabetes Association no longer recommends that pregnant women with low risk factors be screened for gestational diabetes mellitus. However, this recommendation was not based on outcome data confirming the safety of this approach. To address this concern, Moses and colleagues conducted a study to determine the prevalence of gestational diabetes and the pregnancy outcomes in women with low risk factors compared with other women with gestational diabetes.
A total of 2,907 Australian women in the third trimester of a singleton pregnancy were screened for gestational diabetes with a 75-g glucose load after an overnight fast two hours after the load was administered. Women were considered at low risk if they were younger than 25 years, had a body mass index of less than 25 kg per m2 and were from a Caucasian background.
The study population included 573 women who were considered at low risk. Of these, 16 women (2.8 percent) had gestational diabetes. This represented 8.7 percent of all women identified with diabetes in this study. If women with a family history of diabetes were excluded from the low-risk category, 2.5 percent of low-risk women were found to have gestational diabetes. If the definition of low body mass index is expanded to include women at less than 27 kg per m2, 9.8 percent of the women determined to have gestational diabetes would have been from this low-risk group. There were no differences in birth weight, morbidity or rates of emergency cesarean section in women from the low-risk group compared with other women with gestational diabetes.
The authors conclude that although there is less risk of gestational diabetes in low-risk women, the prevalence is still high enough to make testing for gestational diabetes worthwhile. Furthermore, low-risk women with gestational diabetes are at equal risk for complications. Therefore, the authors believe that screening pregnant women with low risk factors for gestational diabetes is still warranted in the community they studied. The recommendation not to test women from a low-risk group requires further evaluation in different populations before it can be endorsed.
CLARISSA C. KRIPKE, M.D.
Moses RG, et al. Gestational diabetes: Do lean young caucasian women need to be tested? Diabetes Care November 1998;21:1803-6.
EDITOR'S NOTE: In this Australian community, a significant number of women with gestational diabetes would have been missed if all pregnant women were not screened. The epidemiology of gestational diabetes may be different in the United States. However, as was the case in Australia, even if the prevalence of diabetes is small in low-risk women in the United States, it may not be insignificant. Therefore, family physicians should be cautious about adopting the American Diabetes Association recommendations for selective screening.
C.K.
Evaluating Breast Masses in Women Younger than 40
Breast masses in women younger than 40 years are usually benign. However, distinguishing a benign from a malignant lesion is often difficult because of the density or nodularity of normal glandular breast tissue in younger women. Furthermore, the use of mammography in this age group is associated with a large number of false-negative results. Consequently, the decision to perform a biopsy is usually based on clinical findings, not the results of imaging studies. Morrow and colleagues conducted a retrospective review to (1) determine how often a physician or patient-identified breast mass is confirmed by surgical evaluation; (2) determine how often mammography or ultrasonography in young women with benign clinical examinations identified clinically significant disease; and (3) evaluate the yield of fine-needle aspiration cytology in this group of younger women.
Patients included in the study were women younger than 40 years of age who were identified as having a breast mass. A mass was considered clinically benign if the borders were well-circumscribed and the lesion was mobile and firm. A breast mass was considered suspicious if it was hard, had irregular borders and was poorly mobile. The women were referred to one of four surgeons for further evaluation. Patients who underwent a biopsy before surgical evaluation were excluded. Outcome information, including the use of imaging studies and biopsy results, was obtained by follow-up chart review.
Management of the Young Patient with a Possible Breast Mass* *--Decision regarding surgical excision or clinical follow-up of solid, clinically benign mass is made with patient after discussion of risks and benefits of each approach and her preferences.
BSE=breast self-examination; US=ultrasound; FNA=fine-needle aspiration
Algorithm for the management of a young patient with the finding of a breast mass. Adapted with permission from Morrow M, Wong S, Venta L. The evaluation of breast masses in women younger than forty years of age. Surgery 1998;124:634-41. A total of 605 patients were studied. The mean age of these women was 29 years (range: 17 to 39 years). A family history of breast cancer was reported by 33 percent of patients. In 484 women (80 percent), the mass was found during self-examination or was an incidental finding. In 121 patients, the mass was found by a primary care physician.
Surgical examination determined that 176 of the 484 patient-detected masses (36 percent) were clinically significant and that 35 of the 121 masses (29 percent) detected by a primary care physician were found to be dominant breast masses (defined as a three-dimensional abnormality that is different from surrounding breast tissue). This difference was not significant.
A total of 196 breast biopsies and 15 fine-needle aspirations were performed in the patients whose masses were confirmed by a surgeon. Carcinoma was found in 28 patients, including 22 of the patient-detected masses and six of the physician-detected masses. Fibroadenoma was the most frequent benign diagnosis in both groups. Breast cysts were rarely found on biopsy, accounting for 0.8 percent of masses found by physicians and 2.9 percent of those found by patients.
In evaluating the use of breast imaging studies, the authors obtained 301 studies, including mammography, ultrasonography, or both, that were performed in 438 patients who had either a normal breast examination or a mass thought to be benign on examination by the surgeon. Abnormal results were noted in 112 of the imaging studies; however, the majority of these were considered of low suspicion and required only six-month follow-up. Forty-four of the imaging studies were considered suspicious enough to warrant a biopsy. Fibroadenoma accounted for 34 of the 44 abnormalities identified. Two cases of ductal carcinoma in situ were identified by mammography. These two cancers were incidental findings and not related to the breast mass for which the study was ordered.
A total of 126 women underwent fine-needle aspiration, including 75 patients thought by the surgeon to have a benign mass. None showed malignancy, and five were determined to be atypical. Four of these five women had excisional biopsies, all of which were negative for cancer. Of the 38 women undergoing fine-needle aspiration who were thought by the surgeon to have a significant or dominant breast mass, malignancy was detected in 12. These patients underwent surgical excision. Eight patients had benign cytologic findings, and all underwent excisional biopsy, as did the 18 patients with nondiagnostic cytologic findings.
The authors conclude that the findings of this study indicate that detection of a breast mass by a patient is at least as reliable as detection by a primary care physician. If the examination is thought by a surgeon to be normal or benign, the use of fine-needle aspiration or imaging studies adds very little information. The authors also found that a family history of breast cancer resulted in more biopsies but did not identify a greater number of cancers. In most patients, physician follow-up is all that is necessary. If there is clinical uncertainty in patients younger than 40 years, an ultrasound examination to determine if a mass is present is the appropriate imaging procedure.
JEFFREY T. KIRCHNER, D.O.
Morrow M, et al. The evaluation of breast masses in women younger than forty years of age. Surgery October 1998;124:634-41.
Corticosteroids vs. Physical Therapy for Shoulder Pain
Pain and stiffness of the shoulder are common complaints in patients who visit family practices, but there is little consensus about the optimal therapy for this condition. The two principal treatments are local injection of a corticosteroid or referral for physical therapy. Van der Windt and colleagues conducted a randomized, controlled trial to compare the effectiveness of these two approaches.
Adults who presented to one of 60 Dutch general practices because of pain and restriction of movement in one shoulder were included in the study. Exclusion criteria included concurrent serious medical conditions and any history of surgery, significant trauma, recent injection or physical therapy to the shoulder. All patients were assessed by one physical therapist to confirm that they met the criteria for the study. Of the 109 patients enrolled in the study, 56 were randomly assigned to receive physical therapy and 53 were assigned to undergo treatment with corticosteroid injections.
Physical therapy consisted of 12 sessions, each lasting 30 minutes and including passive joint mobilization and exercise. Treatment could be adjusted depending on symptoms, and use of ice, hot packs or electrotherapy was permitted for relief of pain. Triamcinolone acetonide, in a dosage of 40 mg, was injected intra-articularly by the posterior route using standardized techniques. Patients in the injection group could receive up to three injections during the study period. Patients could continue medications that they were taking before the intervention started and could use analgesics for severe pain during the study. Patients were assessed at three, seven, 13, 26 and 52 weeks by an observer who was blinded to the treatment group assignment. The main outcome measures were self-report of pain and dysfunction plus clinical assessment, including measurement of mobility restriction using a digital inclinometer.
Treatment was assessed as successful at seven weeks in 40 patients treated with injections (77 percent) compared with 26 of those receiving physical therapy (46 percent). All outcome measures were significantly better in patients undergoing injection than in those undergoing physical therapy. By 26 and 52 weeks, only small, nonsignificant differences existed between the two groups. Approximately one half of all patients in each group reported adverse effects, especially pain, following treatment, but these were mild.
The authors conclude that injection with a corticosteroid provided superior treatment in patients with painful stiff shoulder syndrome.
ANNE D. WALLING, M.D.
van der Windt DA, et al. Effectiveness of corticosteroid injections versus physiotherapy for treatment of painful stiff shoulder in primary care: randomised trial. BMJ November 7, 1998;317:1292-6.
Is Laparoscopic Surgery Safe in Postpartum Women?
During pregnancy and the postpartum period, high levels of progesterone increase a woman's vulnerability to gallstone formation. Up to 10 percent of pregnant patients are believed to have gallstones. Biliary tract disease is the second most common nonobstetric surgical problem during pregnancy and the postpartum period. There are concerns that laparoscopic gall bladder surgery may be complicated in the postpartum period because of changes in the biliary tract itself as well as the presence of an enlarged uterus and other intra-abdominal changes. In particular, laparoscopic surgery has been questioned in patients who have undergone a recent cesarean delivery. Diettrich and Kaplan conducted a prospective study to document special considerations for successful laparoscopic biliary surgery in postpartum patients.
The study included 1,100 consecutive patients presenting to a surgical practice with biliary tract disease. Thirty-four of these women had undergone biliary surgery within six weeks of childbirth. All patients had gallstones with symptomatic cholecystitis that met the criteria for surgery. In addition, in 10 (29 percent) of the patients, stones were documented in the ductal system, including one patient who had gallstone pancreatitis. Eight of the women had had a recent cesarean delivery. In these patients, a modified technique was used to obtain pneumoperitoneum, and the intra-abdominal pressure was limited to 10 mm Hg.
Initially, cholangiography was performed selectively but was routinely performed later in the series and led to the diagnosis of two patients with common duct stones who had none of the traditional risk factors. Choledocholithiasis was documented in 50 percent of patients who had preoperative indications for cholangiography and in 18 percent of patients who had no signs or symptoms of stones in the collecting system. Apart from the morbidity caused by common duct stones that were missed early in the study, there was no increase in surgical morbidity, and the average length of hospital stay was 2.6 days. No delayed complications were detected during a mean follow-up of 3.2 years.
The authors conclude that laparoscopic biliary surgery is safe and can be successful in the postpartum period, even in patients who recently delivered by cesarean section. The authors strongly recommend routine cholangiography for postpartum patients because of the high incidence of choledocholithiasis, which may not be clinically apparent.
ANNE D. WALLING, M.D.
Diettrich NA, Kaplan G. Surgical considerations in the contemporary management of biliary tract disease in the postpartum period. Am J Surg September 1998;176:251-3.
Diagnosis of Delirium By Telephone Assessment
Diagnosing delirium in patients who are in non-acute care settings is sometimes difficult logistically, since the assessment of delirium has traditionally required a face-to-face interview. Marcantonio and colleagues conducted a study to determine whether delirium could be diagnosed reliably by telephone in patients who, for whatever reason, cannot be interviewed face-to-face.
Patients who were at least 65 years of age and had been admitted to a hospital for surgical repair of a hip fracture were included in the study. Daily interviews to detect delirium were conducted during the hospital stay, and a telephone follow-up was completed one month after surgery. Patients were excluded from the study if they were unable to use a telephone at baseline or were unable to participate in the face-to-face interviews. A face-to-face interview took place as soon as possible after the telephone interview (range: one to four days).
During the telephone interview and the follow-up face-to-face interview, a Mini-Mental State Examination (MMSE), modified for the telephone interview, a Delirium Symptom Interview (DSI) and a Confusion Assessment Method (CAM) diagnostic algorithm were completed. Patients were classified as having delirium if their CAM assessment results were positive or if they were unable to use a telephone because of confusion (that is, if the patient had experienced an acute decline in cognitive functioning since baseline testing).
The study included a total of 41 patients. Of these, 32 percent had dementia before the hip fracture based on the enrollment interview, 37 percent had postoperative delirium and 10 percent were delirious at discharge. The mean length of hospital stay was six (± four) days. Eight of the 41 patients (20 percent) were considered to be delirious at the time of the telephone interview. After the face-to-face interviews, six of the patients (15 percent) were diagnosed with delirium. All of the patients who were delirious at the one-month follow-up had been diagnosed with delirium at some point during their hospitalization, but not necessarily at hospital discharge. None of the patients who were not delirious at the time of the telephone interview was subsequently judged to be delirious during the face-to-face interview.
The authors conclude that a telephone interview that does not suggest new or recurrent delirium can effectively rule out delirium; however, any evidence of delirium during a telephone interview should be confirmed by a face-to-face evaluation by a physician.
GRACE BROOKE HUFFMAN, M.D.
Marcantonio ER, et al. Diagnosing delirium by telephone. J Gen Intern Med September 1998;13:621-3.
Shortened Hospitalization for DVT with Use of Ardeparin?
Ardeparin, a low-molecular-weight heparin, has recently been labeled by the U.S. Food and Drug Administration for prophylaxis against venous thromboembolism in patients undergoing elective total knee replacement. It has not, however, been evaluated in a randomized controlled trial of patients being treated for established acute deep venous thrombosis (DVT). Goldhaber and associates compared the efficacy of ardeparin and unfractionated heparin in 80 patients with acute symptomatic DVT of the legs that was documented by ultrasound examination.
Patients were randomized to receive one of the following regimens: subcutaneous low-molecular-weight heparin (ardeparin) twice daily during a two-day hospitalization, or a 5,000- to 7,500-unit bolus of unfractionated heparin followed by a continuous intravenous infusion administered for five days or more in the hospital to achieve a target partial thromboplastin time of 1.5 to 2.5 times the upper limit of control. All patients were discharged home with vascular compression stockings and scheduled to return for two- and six-week office visits. The principal efficacy end point was the change on the six-week ultrasound scan compared with baseline. A total of 75 patients underwent follow-up ultrasonography.
No deaths or recurrent DVT occurred in either group. One case of symptomatic, hemodynamically stable pulmonary embolism was diagnosed by high-probability lung scan in a patient assigned to the heparin-treated group. One patient in each group had a major bleeding complication.
Thirty-one of the patients treated with ardeparin improved (79 percent), compared with 21 of the patients treated with unfractionated heparin (58 percent). Hospital costs were greater in the unfractionated heparin group, which averaged 5.7 days of hospitalization compared with the ardeparin group, which averaged 2.2 days of hospitalization. The mean hospital charges were $6,500 and $2,815, respectively. On a satisfaction scale of 1 to 5, with 1 being excellent and 5 being poor, both groups reported an average score of 1.3 for the care they received. Two weeks after treatment, members of both groups were achieving the same level of activity.
Results of this study indicated that, in terms of thrombus resolution, efficacy was greater with ardeparin than with unfractionated heparin. Safety and patient satisfaction were similar. The principal difference between the two management strategies was the dramatic decrease in hospital costs among the patients in the ardeparin group.
The authors conclude that the beneficial effects of ardeparin for orthopedic surgical prophylaxis might be extended to treatment of established acute DVT. In a dosage more than 2.5 times greater than that used for prophylaxis, ardeparin was demonstrated to be more effective and as safe as unfractionated heparin. The use of ardeparin permitted early hospital discharge, resulting in significant savings. The authors note that their study numbers are small, and these results will need to be validated by a larger trial.
BARBARA APGAR, M.D., M.S.
Goldhaber SZ, et al. Abbreviated hospitalization for deep venous thrombosis with the use of ardeparin. Arch Intern Med November 23 1998;158:2325-8.
Intolerance to Cow's Milk and Constipation in Children
Chronic diarrhea is the most common sign of intolerance to cow's milk in children. In a previous study, Iacono and colleagues demonstrated that constipation may also be a sign of intolerance to cow's milk. They hypothesized that cow's milk may cause perianal lesions and painful defecation, resulting in constipation. In this double-blind, crossover study, they compared the effects of soy milk and cow's milk in children with chronic constipation.
Children younger than six years who had been referred to a subspecialist for treatment of chronic constipation were eligible for the study. Exclusion criteria were anatomic causes of constipation, constipation related to another disorder, prior anal surgery or the use of medications known to cause constipation. Constipation was defined as one bowel movement every three to 15 days, accompanied by abdominal symptoms such as pain with defecation. At baseline, children were being fed regular cow's milk, other dairy products or commercial formula made from cow's milk. Previous treatment with laxatives had been unsuccessful in all of the patients.
Sixty-five patients were included in the study and underwent a detailed history and physical examination, along with laboratory tests for total and milk-specific IgE antibodies and a rectal biopsy. Thirty-two children were then assigned to receive a soy-milk diet and 33 were assigned to receive a diet with cow's milk for the next two weeks. After a one-week washout period, the children's diets were reversed for two weeks. A response was defined as eight or more bowel movements during the two-week treatment period. Following the two study periods, the children with a response to the diet that was free of cow's milk were given the soy-milk diet for another month and then underwent a double-blind challenge with cow's milk. During the challenge, the child was randomly assigned to receive cow's milk or a placebo containing soy milk. Each child was observed closely and the challenge was stopped if there were no bowel movements for 72 hours and the patient had perianal lesions or abdominal pain.
During the first phase, none of the children given cow's milk responded; however, 21 of the children given soy milk responded. All those who had a response had at least one soft bowel movement daily after two to six days, with no discomfort and complete resolution of perianal lesions, erythema and edema. During the second two weeks when the dietary interventions were reversed, 23 children who received soy milk responded, compared with none who received cow's milk. When the 44 children were re-challenged with the double-blind, placebo-controlled component of the study, none who received the soy milk had a reaction, compared with all of those who had been given cow's milk.
The rectal biopsy specimens obtained at baseline showed one or more histologic alterations, including inflammatory changes and infiltration by eosinophils, in all 44 of the children who responded to the soy milk and in 12 children who did not respond. A second biopsy in 20 of the responders, done randomly one month after they began the diet without cow's milk, showed normal histology in eight patients and considerable improvement in 12. At baseline, 31 of the 44 responders also had abnormal results on immunologic testing compared with only four of the children who did not respond.
The authors conclude that chronic constipation can be a sign of intolerance to cow's milk in young children, even though chronic diarrhea remains the most common gastrointestinal manifestation of this intolerance. Hypersensitivity shown on immunologic testing also increased the probability that the constipation was diet-related.
JEFFREY T. KIRCHNER, D.O.
Iacono G, et al. Intolerance of cow's milk and chronic constipation in children. N Engl J Med October 15, 1998; 339:1100-4.
MR Cholangiography for Diagnosing Acute Cholecystitis
Ultrasonography has been the screening test of choice for use in the diagnosis of acute cholecystitis. Although ultrasonography is an effective and easily accessible diagnostic modality, it can depict calculi only in the gallbladder and not in the cystic duct. Being aware of the presence of an impacted calculus within the gallbladder neck or cystic duct is important in identifying patients who may develop serious complications of acute cholecystitis. For this reason, other signs, such as gallbladder wall thickness, fluid collection and enlargement of the gallbladder, have been used to aid diagnosis. Magnetic resonance (MR) cholangiography has proved accurate in the diagnosis of bile duct obstruction and choledocholithiasis. Park and associates evaluated the clinical usefulness of MR cholangiography in the diagnosis of acute cholecystitis.
Thirty-five patients with symptoms of acute cholecystitis underwent both ultrasonography and MR cholangiography before cholecystectomy. The images were evaluated, and the results were compared with surgical findings with respect to gallbladder wall thickness and the presence and location of calculi.
Ultrasonography depicted only one of the seven cystic duct calculi (14 percent), but MR cholangiography depicted all of the calculi. There were no false-negative results on cholangiography. One cystic duct calculus suggested on cholangiography was not found at surgery. Fourteen patients had a calculus impacted within the gallbladder neck. Two of the calculi were not demonstrated on ultrasonography. MR cholangiography showed all of the gallbladder neck calculi, and there were no false-negative or false-positive results on imaging of the gallbladder neck.
Eleven patients had floating calculi within the gallbladder lumen. Ultrasonography depicted all of these calculi, but MR cholangiography failed to depict one of them. On a patient-for-patient basis, ultrasonography demonstrated a sensitivity of 62 percent in the diagnosis of cystic duct obstruction, a specificity of 100 percent and an accuracy of 77 percent. MR cholangiography demonstrated a sensitivity of 100 percent, a specificity of 93 percent and an accuracy of 97 percent. In the 29 patients with surgically confirmed thickening of the gallbladder wall, ultrasonography demonstrated a sensitivity of 96 percent, a specificity of 83 percent and an accuracy of 94 percent. MR cholangiography demonstrated a sensitivity of 69 percent, a specificity of 83 percent and an accuracy of 71 percent.
Results of this study demonstrated 100 percent sensitivity for MR cholangiography in the diagnosis of both cystic duct calculi and gallbladder neck calculi. This is much better than the 14 percent and 86 percent sensitivity demonstrated with ultrasonography. The precise location of the calculi was visualized on MR imaging but not on ultrasonography. The Murphy sign, which is useful in the diagnosis of acute cholecystitis on ultrasonography, is not demonstrated on cholangiography. Thus, MR cholangiography should be accompanied by clinical symptoms, laboratory data or ultrasonography to help accurately distinguish acute cholecystitis from chronic cholecystitis.
The authors conclude that MR cholangiography is superior to ultrasonography in the depiction of the causes of cystic duct obstruction, especially cystic duct calculi and calculi in the gallbladder neck. Cost effectiveness of MR cholangiography in this situation remains to be determined. However, when ultrasonography is not diagnostic, MR cholangiography can contribute to management and planning in patients who may develop serious complications of acute cholecystitis.
BARBARA APGAR, M.D., M.S.
Park MS, et al. Acute cholecystitis: comparison of MR cholangiography and US. Radiology December 1998; 209:781-5.
Increasing Screening Accuracy in Patients with Dementia
Because of recent advances in treatment options, accurate assessment and diagnosis of dementia takes on a new significance. Since cognitive impairment is the central symptom of this disorder, screening devices have been developed to identify patients earlier in the disease process. Two of these screening devices include the Mini-Mental State Examination and the Informant Questionnaire on Cognitive Decline in the Elderly. The latter device is a 16-item questionnaire that is completed by a person who knows the patient well. Mackinnon and Mulligan studied the effectiveness of combining these two instruments to screen for cognitive impairment.
Study participants presented to a geriatric hospital or memory clinic without an established diagnosis of dementia. Patients were 62 to 98 years of age; 76 were women and 30 were men, and 59 had not completed high school. Each patient was given a Mini-Mental State Examination, and a person who knew the patient well completed the Informant Questionnaire on Cognitive Decline in the Elderly. Patients were also evaluated to determine whether they met the criteria for dementia as given in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV).
Fifty-eight patients met DSMIV criteria for dementia. The mean score for the Mini-Mental State Examination was 22.5, and the mean score for the informant questionnaire was 3.87. The mean scores for patients diagnosed with dementia differed substantially from those of patients who were not diagnosed with this disorder. Each screening device identified a significant number of the patients with dementia, but combining the results of the two tests improved the percentage of patients with dementia who were identified.
The Mini-Mental State Examination and the Informant Questionnaire on Cognitive Decline in the Elderly appeared to be complementary components in the assessment of geriatric patients who may have dementia. Used together, the tests provided more information than either test used alone.
The authors conclude that while each screening device has some advantages, a combination of the two can improve the accuracy of diagnosis of dementia. Both instruments are easy to use in the clinical setting and can improve the quality of screening for dementia.
KARL MILLER, M.D.
Mackinnon A, Mulligan R. Combining cognitive testing and informant report to increase accuracy in screening for dementia. Am J Psychiatry November 11, 1998;155: 1529-35.
Effect of Beta Blockers in Chronic Heart Failure
It has been shown that the use of beta-adrenergic blockers prevents the adverse effects of sympathetic stimulation on the failing heart. Beta blockade has produced favorable results in a large number of randomized, controlled trials. Although two meta-analyses of the effect of beta blockers in heart failure have been published, the emphasis was on rates of mortality, and data from some nonrandomized or uncontrolled trials were included. Lechat and associates combined the results of 18 published double-blind, placebo-controlled and parallel-group trials to include measures not reported in the original publications.
The 18 trials enrolled a total of 3,023 patients with heart failure that was caused by idiopathic dilated cardiopathy and ischemic heart disease. For all end points, there was a significant effect in favor of treatment with beta blockers. Patients taking beta blockers experienced a 32 percent reduction in the risk of death and a 41 percent reduction in hospitalizations compared with the placebo-treated patients. Patients receiving beta blockers also showed a 32 percent improvement in NYHA classification and were 30 percent less likely to have worsening symptoms. The ejection fraction increased by 29 percent in patients treated with beta blockers compared with placebo-treated patients.
Assuming a treatment period identical to the mean duration of follow-up (seven months), the authors determined that physicians would need to treat 38 patients to avoid one death, 24 patients to avoid one hospitalization and 15 patients to avoid one combined end point.
The effects of treatment in trials of nonselective beta blockers were compared with those in trials of beta1-selective agents. The risk of death was reduced by 49 percent in trials of nonselective beta blockers but by only 18 percent in trials of beta1-selective agents. This difference was statistically significant.
The meta-analysis indicates that the use of beta blockers is associated with a reduction in mortality of about 30 percent in patients with heart failure. Any uncertainty about the effect of beta blockers on rates of survival is heightened by the finding that the magnitude of the mortality reduction depends on the pharmacologic properties of the drug used. While selective and nonselective beta blockers increased ejection fractions and decreased hospitalizations in a similar way, nonselective beta blockers were associated with a larger survival benefit than beta1-selective agents. This observation is especially noteworthy because data from postinfarction trials have suggested that agents that block both beta1 and beta2 receptors may provide more complete protection against catecholamine toxicity than agents that act only on the beta1 receptor.
It should be noted that nearly 90 percent of the experience with nonselective beta blockers is with carvedilol, which is known to block alpha-adrenergic receptors in addition to beta1 and beta2 receptors. It is possible that blockage of alpha receptors might account for the larger reduction in mortality observed with nonselective agents in the present analysis.
The authors conclude that unlike other meta-analyses, this analysis did not confine itself to mortality but rather analyzed nonfatal measures of outcome such as hospitalizations. For these variables, the number of events was large and the treatment effects were robust. This meta-analysis demonstrates that the addition of a beta blocker to conventional therapy is associated with hemodynamic and symptomatic improvement as well as favorable effects on morbidity and mortality. Physicians have sufficient evidence to support the use of beta blockers in heart failure.
BARBARA APGAR, M.D., M.S.
Lechat P, et al. Clinical effects of ß-adrenergic blockade in chronic heart failure. A meta-analysis of double-blind, placebo-controlled, randomized trials. Circulation September 22, 1998;98:1184-91.
Ductal Carcinoma in Situ of the Breast: Not a Single Entity
Ductal carcinoma in situ of the breast is malignant transformation of epithelial cells of the ductolobular system, without invasion through the basement membrane. Classically, ductal carcinoma in situ has presented as nipple discharge or a palpable mass. Until recently, the condition was regarded as an uncommon form of breast malignancy (representing about 1 percent of new breast malignancies) that was best treated by mastectomy. A review by Silverstein emphasizes that the incidence of ductal carcinoma in situ is increasing, and it is now known to be a heterogeneous group of conditions with a range of management options and prognoses.
Approximately 36,000 new cases of ductal carcinoma in situ are diagnosed each year in the United States, representing 17 percent of all breast cancers. Most cases are detected by mammography and occur in asymptomatic women. Several classifications are currently used according to histologic structure, nuclear grade, presence of necrosis and other factors. The experimental Van Nuys prognostic index is a scoring system based on recurrence data from a large series of patients that takes into consideration the nuclear grade and the presence of necrosis. Also, three predictors of recurrence (tumor size, margin width and pathologic classification) are given a score from one to three and then combined to estimate the prognosis as a numerical score from three (best) to nine (worst).
Classification and prognosis are particularly important in ductal carcinoma in situ because of the many controversies concerning management. In this series, the chance of invasive recurrence eight years after diagnosis was 7 percent, with a 1.4 percent risk of death from breast cancer. Only about 40 percent of low-grade lesions become invasive over a span of 25 to 30 years if left untreated. Approximately one half of all local recurrences become invasive.
Current treatments range from tumor excision to mastectomy. The width of the disease-free margin in the excised tissue is the most important factor in prognosis. Several studies have indicated that recurrence is minimal if margins of at least 10 mm are achieved. The role of radiotherapy following excision has become controversial. Although earlier studies clearly indicated an improved prognosis with postoperative radiotherapy, there is now considerable interest in subgroups of patients in whom the advantages of radiotherapy may be outweighed by side effects, cost and adverse factors. In particular, radiotherapy may change the texture of breast tissue, complicating mammographic detection of recurrence. Decisions about the extent of surgery and the use of radiotherapy must be made on an individual basis--but all patients with ductal carcinoma in situ of the breast must be clinically followed for life to ensure prompt recognition of any recurrence.
ANNE D. WALLING, M.D.
Silverstein MJ. Ductal carcinoma in situ of the breast. BMJ September 12, 1998;317:734-9.
New Drugs for Rheumatoid Arthritis: Are They Better?
Consultants for The Medical Letter for Drugs and Therapeutics reviewed three new drugs for the treatment of rheumatoid arthritis. Leflunomide, which inhibits pyrimidine synthesis, and etanercept, which blocks action of tumor necrosis factor, have recently been labeled by the U.S. Food and Drug Administration (FDA) for use in rheumatid arthritis. A third drug, infliximab, which also blocks tumor necrosis factor, was previously labeled for treatment of Crohn's disease.
Leflunomide is an oral drug considered as a possible alternative to methotrexate for first-line treatment of rheumatoid arthritis. The active metabolite of leflunomide inhibits the enzyme required for synthesis of pyrimidine nucleotide. It has an antiproliferative effect on T cells in vitro and an anti-inflammatory effect in animals. The active drug is metabolized and excreted in urine and feces. It has a half-life of about 14 days.
Unpublished 12-month study data indicate that after one year, an improvement of greater than 20 percent in tender and swollen joints occurred in 41 percent of patients treated with leflunomide in a dosage of 20 mg per day; in 35 percent treated with methotrexate in a dosage of 7.5 to 15 mg per week; and in 19 percent of those given placebo. Another study demonstrated that more patients improved with leflunomide therapy than with sulfasalazine or placebo.
Leflunomide inhibits CYP2C9, which could lead to an increase in serum concentrations of many drugs, including ibuprofen, tolbutamide and diclofenac. Concurrent use of cholestyramine leads to rapid decreases in serum levels of leflunomide. Adverse effects include diarrhea and reversible alopecia. The drug is carcinogenic and teratogenic in animals and is contraindicated in pregnancy. The oral dosage of leflunomide is 100 mg daily for three days followed by a maintenance dosage of 10 to 20 mg daily. The cost to the pharmacist is about $1,600 for a six-month prescription of leflunomide at a dosage of 10 to 20 mg per day.
Etanercept is an injectable drug marketed for use alone or with methotrexate for patients with active disease that is refractory to methotrexate or other antirheumatic drugs. Infliximab is given intravenously and, presumably, it will also be marketed for use in refractory disease. Etanercept is a recombinant version of soluble human tumor necrosis factor receptor, and infliximab is an anti-tumor necrosis factor monoclonal antibody. Both bind to tumor necrosis factor and prevent its binding to cell surface receptors. A single subcutaneous 25-mg dose of etanercept has a half-life of about five days compared with a single infusion of infliximab, which has a half-life of about 10 days.
Randomized trials of patients with refractory disease demonstrated improvement in symptoms in 75 percent of patients undergoing therapy with etanercept, compared with 14 percent of control subjects. In a similar trial, infliximab improved symptoms in refractory patients up to 79 percent of the time, compared with 8 percent of the time in control subjects.
Reactions at the injection site are common with etanercept. Patients treated with the drug have developed auto-antibody markers, but no autoimmune disease developed after one year of therapy. Some patients undergoing therapy with infliximab developed hypersensitivity reactions. The dosage of etanercept is 25 mg subcutaneously twice a week, and the wholesale price for a six-month supply would be $6,300. Infliximab is given intravenously in dosages of 3 or 10 mg per kg, repeated at about four- to 12-week intervals. The cost of three doses would be about $3,500 to $10,500 for a 60-kg (132-lb) patient.
The Medical Letter consultants conclude that leflunomide improves the signs and symptoms of rheumatic arthritis and slows the progression of disease but offers no clear advantages over better known and less expensive drugs such as methotrexate. Etanercept and infliximab appear to decrease symptoms in active disease that is refractory to other drugs, but whether they slow disease progression is unknown. It is not known at this time whether the latter two drugs will increase the incidence of other autoimmune diseases, serious infections or malignancy.
BARBARA APGAR, M.D., M.S.
Medical Letter consultants. New drugs for rheumatic arthritis. Med Lett Drugs Ther November 20, 1998; 40 (1040):110-2.
Comparing Three Therapies for Treatment of Back Pain
Low back pain is a common patient complaint and continues to cause concern because of the high cost of treatment and lost productivity. Despite the availability of many nonsurgical treatment options, very few have proved effective. Cherkin and colleagues conducted a randomized study to compare the effectiveness of physical therapy, chiropractic manipulation and patient education in decreasing symptoms, improving function and decreasing long-term recurrence of low back pain.
Patients between the ages of 20 and 64 years who saw their primary physician for treatment for low back pain and still reported pain one week later were eligible for the study. Among the exclusion criteria were a history of back surgery, sciatica, osteoporosis, vertebral fractures or involvement in litigation or in a claims action for compensation related to a back injury. Patients who met all the study criteria were randomized into one of three groups. Patients in group 1 received physical therapy, patients in group 2 received chiropractic manipulation and patients in group 3 received a patient education booklet. There were only a few significant differences in baseline characteristics among the groups: patients assigned to the manipulation group were less likely to have sought chiropractic care previously; patients in the physical therapy group had the most bothersome symptoms; and patients in the group receiving only the patient-education booklet reported fewer days with restricted activities. Patients in the physical therapy group were taught exercises to "centralize" symptoms and to avoid movements that "peripheralize" them, as specified by the McKenzie approach. Adjunctive treatments, such as heat, ice, nerve stimulation or ultrasonography, were not used. Patients in the manipulation group received the most common type of chiropractic treatment, along with advice about exercise and activity. A consultant monitored the chiropractors' compliance with the treatment protocol. Patients in the education group received a booklet that described the causes of back pain, prognosis, appropriate use of imaging and the role of specialists, and a list of activities to promote recovery. Both long- and short-term outcomes were measured, including the effectiveness of the intervention on the current episode of back pain, the levels of function and disability, and the recurrence of pain.
The inclusion criteria were met by 323 patients. Mean patient age was 40 years, and the distribution between men and women was almost equal. Most patients had been treated previously for back pain and had had back pain for less than six weeks. After four weeks, patients in the two treatment groups reported a significant decrease in severity of symptoms compared with those in the education group. However, these differences did not remain statistically significant at 12 weeks. Evaluation of disability scores revealed that after one year, the differences among the three groups were minimal. The type of treatment received appeared to have no effect on patients' symptoms or function, including days of missed work. In addition, approximately 50 percent of all patients experienced a recurrence of back pain at one year and 70 percent experienced a recurrence during the second year. The only significant difference among the groups was in the assessment of care, with 75 percent of patients in chiropractic and physical therapy groups rating their care as "very good" or "excellent," compared with only 30 percent in the education group. Of note, however, were differences in time and cost of care. The total time spent with a chiropractor or physical therapist was about 2.5 hours. The total cost of care to the HMO for treatment of low back pain over a two-year period differed by less than 2 percent in the chiropractic and physical therapy groups and was almost three times higher than the cost incurred by the group receiving the patient education booklet. Patients in the education group also spent less for other health care services to treat their low back pain.
The authors conclude that physical therapy or chiropractic manipulation for treatment of patients with low back pain offers minimal benefit, and there appears to be no advantage to the use of one treatment over the other. The primary benefit of treatment seems to be increased patient satisfaction and a decrease in the bothersomeness of symptoms at four weeks. However, whether the small benefits of treatment are worth the cost is a matter of debate. Future research is needed to identify which subsets of patients with low back pain are most likely to benefit from one or both types of treatment.
JEFFREY T. KIRCHNER, D.O.
Cherkin DC, et al. A comparison of physical therapy, chiropractic manipulation, and provision of an educational booklet for the treatment of patients with low back pain. N Engl J Med October 8, 1998;339:1021-9.
Montelukast for Exercise-Induced Bronchoconstriction in Children
Exercise-induced bronchoconstriction occurs in 80 to 90 percent of children with asthma and can interfere with activities important for social and physical development. Current recommendations for prevention of exercise-induced bronchoconstriction include administration of short-acting beta2-adrenergic agonists or cromolyn before exercise. Montelukast, a leukotriene receptor antagonist, increases ciliary activity and decreases mucus secretion, venopermeability and eosinophil migration into airways mucosa. Kemp and associates conducted a randomized, double-blind, placebo-controlled crossover study of the effects of montelukast on exercise-induced bronchoconstriction in children with asthma.
The 25 children in the study ranged in age from six to 14 years. They received either montelukast (given in a 5-mg chewable tablet) or placebo once daily in the evening for two days before the exercise challenge. A standardized treadmill exercise challenge was performed approximately 20 to 24 hours after the second dose. Spirometry measurements were obtained 20 and five minutes before the exercise challenge and then at five, 10, 15, 30, 45, 60 and, if necessary, 75 and 90 minutes after exercise.
When compared with placebo, montelukast was associated with a significant reduction in the maximum percentage of fall in the forced expiratory volume in one second (FEV1). Moreover, the time until recovery was shorter following administration of montelukast, although the difference between montelukast and placebo did not reach statistical significance. Fourteen adverse clinical events were noted (eight in the placebo treatment period and six in the montelukast treatment period). All of them were transient and self-limited.
The authors conclude that montelukast protects against exercise-induced bronchoconstriction throughout the course of a once-daily dosing interval. This therapeutic effect has also been documented in adults during a 12-week treatment period. Montelukast did not, however, provide complete protection against exercise-induced bronchoconstriction in the children studied, as has been reported in previous studies of albuterol and salmeterol. Continuous use of the latter medications has been associated with tolerance. Cromolyn and nedocromil have also demonstrated protection against exercise-induced bronchoconstriction when either agent is administered 15 to 30 minutes before exercise. Beclomethasone has also been shown to provide protection against mild exercise-induced bronchoconstriction in children after one and two months of therapy, but tolerance to the protective effect also developed after three months of therapy.
RICHARD SADOVSKY, M.D.
Kemp JP, et al. Montelukast once daily inhibits exercise-induced bronchoconstriction in 6- to 14-year-old children with asthma. J Pediatr September 1998; 133:424-8.
Metastatic Prostate Cancer: Is Adding Flutamide Beneficial?
Prostate cancer is currently the most commonly diagnosed neoplasm in the United States. The median survival rate in men with metastatic disease ranges from 24 to 36 months. Because the growth of prostate cancer requires androgens, surgical castration is often performed in patients with advanced disease to suppress androgens and provide palliative effect. However, androgens are also produced by the adrenal glands. To counteract the effects of these androgens, agents such as leuprolide acetate and flutamide have been used. In an earlier study, Eisenberger and colleagues found that treatment with a combined androgen blockade of leuprolide acetate with flutamide improved patients' survival. In this double-blind, randomized study, the authors further evaluated the effects of this androgen blockade plus bilateral orchiectomy in the treatment of patients with metastatic prostate cancer.
Eligible patients had confirmed adenocarcinoma of the prostate with bone or distant soft-tissue metastases. All patients underwent early bilateral orchiectomy but received no previous or concomitant hormonal treatment, chemotherapy or biologic-response modifier therapy. Patients were still eligible for the study if they had received palliative radiation at sites of distant metastases. Baseline measurements of serum creatinine, prostate-specific antigen (PSA), liver enzymes, serum alkaline phosphatase, and serum testosterone levels were obtained. These measurements were repeated at one month and then every three months during the trial. Other diagnostic studies included a chest radiograph, a bone scan and a computed tomographic scan of the pelvis and abdomen at baseline and at six-month intervals for two years. Patients were randomized to either a treatment group, where they received two 125-mg capsules of flutamide three times a day until progression of the disease was noted, or a control group. The primary end point was death. Secondary end points included progression-free survival and PSA response.
During the five-year study period, 698 patients were randomly assigned to receive flutamide, and 687 were assigned to receive placebo. Patients had a mean age of 71 years. Twenty-two percent of the patients were black. The mean survival rate in the treatment group was 33.5 months compared with 29.9 months in the placebo group. This difference was not statistically significant. The median progression-free survival time was 20.4 months in the treatment group and 18.6 months in the placebo group. The percentage of PSA responses was higher in the treatment group (74 percent) than in the placebo group (61.5 percent). Despite this finding, patients in the flutamide group did not have better survival rates.
The authors conclude that flutamide offers no additional benefit to patients with metastatic prostate cancer following bilateral orchiectomy. This finding is in contrast to results of their previous study in which they found a 25 percent improvement in median survival in men with metastatic prostate cancer who were given flutamide with leuprolide acetate. In view of this, the authors recommend a reevaluation of medical and surgical options of castration, either alone or in combination with flutamide or other antiandrogen agents. The results cited in this study suggest that the benefits of combined androgen blockade in patients with metastatic prostate cancer are negligible.
JEFFREY T. KIRCHNER, D.O.
Eisenberger MA, et al. Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. N Engl J Med October 8, 1998;339:1036-42.
Is the Timing of Contraceptive Injections Important?
Depot medroxyprogesterone acetate (DMPA) is a highly effective contraceptive when injected during the first seven days of the menstrual cycle. However, recent studies have suggested that DMPA given on days 9 through 11 of the cycle may not suppress ovulation. Because of the difficulty of timing DMPA injections with a patient's cycle, the current recommendation is to provide the injection any time during the menstrual cycle as long as the woman is not pregnant. Petta and colleagues studied the effect of DMPA injections on ovarian function in women who were at days 8 through 13 of the menstrual cycle.
Thirty healthy women between 18 and 40 years of age were enrolled in the study. Exclusion criteria included use of hormonal contraception in the past four months and recent pregnancy or breast feeding. All of the patients were seen and evaluated once during days 8 through 13 of the menstrual cycle. Ovarian function was evaluated by transvaginal ultrasound examination and serum estrogen levels. The women were give 150 mg of DMPA and underwent evaluation for ovulation at days 1, 3 and 7 by repeat ultrasound examinations and serum estrogen and luteinizing hormone levels. Serum progesterone levels were measured at day 7 after the injection and, if the level was more than 2.5 ng per mL (7.9 nmol per L) and follicular rupture was observed by ultrasound, the patients were assumed to have ovulated during the study.
None of the women who were on days 8 or 9 of their cycle ovulated after DMPA injections. One of five women on day 10 of the cycle ovulated, as well as four of 10 women who were on day 11 or 12 of the cycle and all but one of the women on day 13 of the cycle. In all, 30 percent (nine of 30 women) of the women ovulated during the study after an injection of DMPA. All women who ovulated did so within three days of the injection, suggesting that DMPA may trigger ovulation if given close to mid-cycle.
Ovulation suppression with DMPA is related to the timing of administration and women's cycles. During the first seven days after the start of the cycle, it provides good suppression of ovulation. However, if DMPA is given on days 8 through 13 of the menstrual cycle, the injections may not reliably suppress ovulation. The authors conclude that women who receive DMPA injections during days 8 through 13 of the menstrual cycle should use a back-up method of contraception for seven days to reduce the risk of unintended pregnancy.
KARL MILLER, M.D.
Petta CA, et al. Timing of onset of contraceptive effectiveness in Depo-Provera users. II. Effects on ovarian function. Fertil Steril November 1998;70:817-20.
Thromboembolic Events in Association with Atrial Flutter
While the management of atrial fibrillation includes anticoagulation, the value of this treatment for atrial flutter is less well established. Seidl and associates conducted a retrospective study to assess the frequency of thromboembolism in patients hospitalized with atrial flutter as the primary rhythm disorder.
A total of 191 patients with chronic or recurrent atrial flutter, defined as organized atrial tachycardia at a rate of 240 or more beats per minute on a 12-lead electrocardiogram, were included in the study. Electrical cardioversion was performed in 138 patients (72.3 percent), catheter ablation was used in 28 patients (14.7 percent), medical cardioversion was used in 19 patients (9.9 percent) and overdrive stimulation was used in six patients (3.1 percent). Warfarin therapy had been administered in 67 of the patients several weeks before and after cardioversion. An additional 72 patients were receiving aspirin.
Acute embolic events within 48 hours of cardioversion were distinguished from later embolic events during long-term follow-up and before hospital admission. The overall embolic event rate, including a history of thromboembolism, acute embolism and a thromboembolic event during follow-up, was 11.5 percent (22 of the 191 patients). A remote history of a systemic embolic event was found in 5.8 percent (11 of 191 patients). Following direct-current cardioversion, three of 138 patients (2.2 percent) sustained a cerebrovascular incident within 48 hours. During long-term follow-up (about 26 months) nine patients (4.7 percent) had an embolic event.
Three of 67 patients who received effective anticoagulation (4.5 percent) had an embolic event during follow-up. In contrast, 10 of the 124 patients who did not receive anticoagulation (8.1 percent) or who received an ineffective amount incurred an embolic event. Risk indicators for an embolic event included organic heart disease, depressed left ventricular function, hypertension and diabetes mellitus. A history of hypertension was the only independent risk factor.
The authors conclude that the annual risk of an embolic event in patients with atrial flutter is approximately 1.8 percent, approximately one third of the 4.5 percent annual risk in patients with nonrheumatic atrial fibrillation. Anticoagulation therapy may decrease this risk.
In an accompanying editorial, Dunn agrees that atrial flutter poses an increased risk of an embolic event and that anticoagulation is appropriate in patients with this condition. Further study may be useful to determine if different forms of atrial flutter, as determined by the direction of depolarization, may be associated with different risks of thromboembolism.
RICHARD SADOVSKY, M.D.
Seidl K, et al. Risk of thromboembolic events in patients with atrial flutter. Am J Cardiol September 1, 1998; 82:580-3, and Dunn MI. Thrombolism with atrial flutter [Editorial]. Am J Cardiol September 1, 1998;82:638.
"Tips from Other Journals" are written by the medical editors of American Family Physician.
Copyright © 1999 by the American Academy of Family Physicians.
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